This laboratory recently discovered that primary B-lymphocytes can be programmed for the synthesis and delivery of short, non-coding RNAs in vitro and in vivo. In this revised R21 application we intend to rapidly adapt this new concept and test it in the context of tumor therapy to limit or control cancer cell growth and metastasis. miRNA signatures have been identified in both hematological malignancies and solid tumors, distinguishing tumor cells from normal cells. In some instances miRNAs are associated with the prognosis and the progression of cancer. This can happen because of one of two conditions: loss of suppressor miRNAs or overexpression of oncogenic miRNAs. miRNA-based therapy can then be geared at either restore the loss of a particular miRNA or suppress an oncogenic miRNA, respectively. The present proposal aims at gathering first line proof-of-concept that primary B lymphocytes synthesizing and secreting short, non-coding miRNAs can be used to treat cancer in vivo, a new form of therapy that we have termed immunogenomic therapy to typify its hybrid (genomic and immunological) nature. The following three Aims are proposed: (1) Engineer and characterize therapeutic plasmid vectors for miRNA replacement or inhibition; (2) miRNA inhibition: Targeting miR-155 in B leukemic cells; and (3) miRNA replacement: Restoring miR-335 in metastatic breast cancer cells. It is hoped that the work proposed in this high risk/high pay off revised proposal will provide us with the answers needed for a proof-of-principle validation of the new idea. We anticipate that success in obtaining proof-of-concept validation for immunogenomic therapy will open new horizons for the treatment of cancer and metastases.